Striatal Nurr1, but not FosB expression links a levodopa-induced dyskinesia phenotype to genotype in Fisher 344 vs. Lewis hemiparkinsonian rats

Kathy Steece-Collier, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI 49503, USA. Electronic address: kathy.steece-collier@hc.msu.edu.
Timothy J. Collier, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI 49503, USA.
Jack W. Lipton, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI 49503, USA.
Jennifer A. Stancati, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Mary E. Winn, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Allyson Cole-Strauss, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.Follow
Rhyomi Sellnow, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Melissa M. Conti, Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, USA.
Natosha M. Mercado, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Eduardo A. Nillni, Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
Caryl E. Sortwell, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI 49503, USA.
Fredric P. Manfredsson, Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.Follow
Christopher Bishop, Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, USA.

Document Type

Article

Abstract

Numerous genes, and alterations in their expression, have been identified as risk factors for developing levodopa-induced dyskinesia (LID). However, our understanding of the complexities of molecular changes remains insufficient for development of clinical treatment. In the current study we used gene array, in situ hybridization, immunohistochemistry, and microdialysis to provide a unique compare and contrast assessment of the relationship of four candidate genes to LID, employing three genetically distinct rat strains (Sprague-Dawley (SD), Fischer-344 (F344) and Lewis-RT.1) showing differences in dyskinesia susceptibility and 'first-ever LID' versus 'chronic LID' expression in subjects displaying equal dyskinesia severity. In these studies, rat strains were easily distinguishable for their LID propensity with: 1) a majority of SD rats expressing LID (LID+) and a subset being resistant (LID-); 2) all F344 rats readily developing (LID+); and 3) all Lewis rats being LID-resistant (LID-). Following chronic levodopa, LID+ SD rats showed significant increases in candidate gene expression: Nr4a2/(Nurr1) > > Trh > Inhba = Fosb. However, SD rats with long-standing striatal dopamine (DA) depletion treated with first-ever versus chronic high-dose levodopa revealed that despite identical levels of LID severity: 1) Fosb and Nurr1 transcripts but not protein were elevated with acute LID expression; 2) FOSB/ΔFOSB and NURR1 proteins were elevated only with chronic LID; and 3) Trh transcript and protein were elevated only with chronic LID. Strikingly, despite similar levodopa-induced striatal DA release in both LID-expressing F344 and LID-resistant Lewis rats, Fosb, Trh, Inhba transcripts were significantly elevated in both strains; however, Nurr1 mRNA was significantly increased only in LID+ F344 rats. These findings suggest a need to reevaluate currently accepted genotype-to-phenotype relationships in the expression of LID, specifically that of Fosb, a transcription factor generally assumed to play a causal role, and Nurr1, a transcription factor that has received significant attention in PD research linked to its critical role in the survival and function of midbrain DA neurons but who's striatal expression, generally below levels of detection, has remained largely unexplored as a regulator of LID. Finally these studies introduce a novel 'model' (inbred F344 vs inbred Lewis) that may provide a powerful tool for investigating the role for 'dyskinesia-resistance' genes downstream of 'dyskinesia-susceptibility' genes in modulating LID expression, a concept that has received considerably less attention and offers a new ways of thinking about antidyskinetic therapies.

Keywords

FosB, Genes, Levodopa-induced dyskinesias, Nurr1, Parkinson's disease, Striatum

Medical Subject Headings

Animals; Antiparkinson Agents (toxicity); Corpus Striatum (drug effects, metabolism); Dyskinesia, Drug-Induced (genetics, metabolism); Genotype; Levodopa (toxicity); Male; Nuclear Receptor Subfamily 4, Group A, Member 2 (metabolism); Parkinsonian Disorders (genetics, metabolism); Phenotype; Proto-Oncogene Proteins c-fos (metabolism); Rats; Rats, Inbred F344; Rats, Inbred Lew

Publication Date

8-1-2020

Publication Title

Experimental neurology

E-ISSN

1090-2430

Volume

330

First Page

113327

PubMed ID

32387398

Digital Object Identifier (DOI)

10.1016/j.expneurol.2020.113327

This document is currently not available here.

Share

COinS